The prevailing model of conscious memory holds that a group of loosely related structures, collectively called the medial temporal lobe (MTL), work together as a single functional unit. According to this current orthodoxy, the structures in the MTL are thought to store the memory of specific objects, facts and events. This model has many adherents despite the fact that it is contradicted by a large body of empirical data. We have developed a competing hypothesis, which is consistent with these data. Our model holds that different structures within the MTL have different functions, and that their collective functions extend beyond those assigned to the MTL by the orthodox model. Specifically, work in this project has shown that the perirhinal cortex, one small component of the MTL, operates as a part of the object-analyzer pathway of the visual cortex. We have further shown that apparent inconsistencies in the effects of perirhinal cortex lesions on visual discrimination learning can be explained by considering the hierarchical organization of representations in the visual system. On this view, caudal parts of visual cortex represent simple features, whereas more rostral regions, including the perirhinal cortex, represent more complex conjunctions of features. We call this the perceptual-mnemonic/feature-conjunction model of perirhinal cortex function, and it presents several major challenges to the orthodox view of memory systems. One of these involves the distinction between a fast learning and slow learning system. We have explained that the distinction between episodic memory and semantic memory, often ascribed to hippocampal versus extra-hippocampal parts of the MTL, can be better understood in terms of fast versus slow learning (Murray and Wise, 2010). This idea was supported by our earlier work, which showed that removal of the hippocampus plus underlying cortex (Murray and Wise, 1996) or transection of the fornix (Brasted et al. 2005) severely disrupted fast (one-trial) learning of the associations between images and actions, also known as visuomotor learning (VML). There is evidence that the hippocampal system is not necessary for PAL. Murray et al. (1993) found that PAL was unaffected by complete removal of the hippocampus. This could mean that the hippocampal system is uninvolved in associative learning when neither component of the association has a relevant spatial attribute. But recent work appears to rule out that account (Brasted et al., 2002, 2003, 2005). Previous work on this project showed that hippocampal-system damage (fornix transection) impaired fast learning of object-response associations even when both the visual stimuli and the responses were nonspatially differentiated. This finding points to another possibility for the results described by Murray et al. (1993). On this explanation of our PAL results, there was no deficit because subjects learned the paired associates slowly. This hypothesis predicts that hippocampal-system damage might cause deficits in the fast learning of paired associates. Accordingly, we are engaged in testing the role of the hippocampus in PAL using a fast-learning procedure. The rationale for this test is the theory that the hippocampal system functions as a rapid acquisition, pattern-associator network, whereas the neocortex acquires similar information, but more slowly. In the context of PAL, this theory implies that the perirhinal cortex, a neocortical area, subserves the slower form of learning and that the hippocampal system subserves the faster form. We have now developed procedures that allow subjects to acquire both VML and PAL associations rapidly, within a single testing session. The results from this project could resolve crucial issues about hippocampal and perirhinal cortex function. A second goal of this project is to determine what part of the hippocampal system (hippocampus proper, subicular complex, or entorhinal cortex) is essential for fast VML. A third goal is to test hippocampal-prefrontal interactions in fast associative learning. We predict that both direct (via the fornix) and indirect (via entorhinal cortex) outputs of the hippocampus to the prefrontal cortex are critical to these kinds of rapid learning. We have also studied hippocampal-prefrontal interactions with diffusion-tensor imaging (DTI). DTI is a means of assessing presumptive white matter alterations in the brain. Although the brain substrates for object memory are frequently studied with lesion techniques, the distal effects of such lesions on other memory-related brain regions remain largely unknown. The project used DTI to examine the effects of excitotoxic hippocampal lesions on white matter tracts. DTI analyses were carried out in the corpus callosum, fornix, white matter of the temporal stem, the cingulum bundle, the subcortical white matter of the ventromedial prefrontal cortex, and the optic radiations. The results showed that only white matter in the fornix and in the region of the ventromedial prefrontal cortex were altered by the lesion (Shamy et al., 2010). The successful use of DTI in this project demonstrates that it will be a valuable tool for investigating temporo-frontal interactions.